CN101389297A - Adsorbent-containing hemostatic devices - Google Patents

Abstract

The present invention utilizes a combination of a porous carrier and an adsorbent such as a molecular sieve or an inorganic material selected from the group consisting of diatomaceous earth, glass powder or fibers, precipitated or fumed silica, kaolin and montmorillonite clays, and Ca exchanged permutites to make a more effective hemostatic device to treat wounds in mammalian animals. These hemostatic devices provide a lower heat rise to the skin as compared to direct application of zeolites to the skin.

Description

The hemostasis device that comprises adsorbent

Background of invention

The present invention relates generally to the hemostasis purposes of inorganic material and adsorbent.Concrete, the present invention relates to be incorporated into inorganic material and adsorbent in adsorbing medium such as non-woven material or the thin film, exist these adsorbents of capacity to stop blood loss in this adsorbing medium, will raising because of the temperature that adsorbent causes the absorption of water simultaneously, it is minimum to drop to.

According to the treatment tendency, usually wound is divided into acute wounds or chronic wounds.The acute wounds that is caused by wound or surgical operation comprises the wound such as active hemorrhage wound point, for example has detectable, the wound of clotted blood not.In treatment of wounds, extremely important to the local quick control of bleeding of active hemorrhage wound point, especially for the processing of wound, the wound that causes of military exercises or surgical operation for example.

Conventional hemostasis method, for example hand, burn or sew up both consuming time, be not again effectively control over bleeding of total energy.Because septic yanks all will face Combat Condition every day, it causes the wound with massive blood loss, thereby wound processing is recently greatly paid close attention to.In many cases, the individuality that may survive from initial injury is only dead because lose blood.Recognize the middle cardiac status in the reason of injury outside of stopping blooding, a large amount of attention focused on development can cause rapidly condense, stop blooding, with wound surface form combine closely, accelerate to form a scab and with the product of host (host) tissue compatible.At present, the product that is using several classes to be distinguished by the mechanism of action.First type comprises the material of accelerating condensation process by the moisture in the absorbing blood.Such product comprises basic cotton yarn (basic cotton gauze).From Johnson ﹠amp; The product of Johnson ' s Ethicon company also belongs to this type, and the said firm sells its various forms of Surgicel ^TMThe regenerated cellulose product line.The product that on market, also has other cellulose types.Second type product is attempted to improve the active feature of coagulating enzyme and strengthen and condense by increasing.This series products can comprise following composition, for example: thrombin, Fibrinogen, propyl gallate, aluminum sulfate, full acetylated glycosamine and episilon amino caproic acid.Other hemorrhages are difficult to adhere to moistening tissue, and the shortage clot can adherent framework.Proved the zeolite based QuikClot of Z-Medica ^TMProduct is effectively in hemostasis, but may make patient be exposed to excessive heat, and the product needed of using this powder type rinses out this product after finishing condensing from wound.

In the product of these prior aries each all to have an aspect at least be incomplete.Only to be beneficial to aspect the agglomerative blood constituent (as platelet, erythrocyte and blood plasma) often be not selective especially to the product that works by the moisture in the absorbing blood concentrating, thus this series products enhancing condense aspect not as other products effective.Second type product condenses by the active enhancing that becomes to assign to of interpolation such as the raising coagulating enzyme of thrombin, Fibrinogen, propyl gallate, aluminum sulfate, full acetylated glycosamine and episilon amino caproic acid.Though these products can stop blooding very effectively, but they also can be very expensive, restriction with pot-life, and in these compositions source under animal or human some situation, these products may provide pathogen transfer or anaphylactoid approach.In the third product type, the existence of HemCon product has short and expensive problem of potential anaphylaxis side effect, pot-life.There is the problem of high heat of adsorption in described Z-Medica QuikClot product, and this high heat of adsorption can cause user very uncomfortable, and limits its use at the thermo-responsive position of health.Though it is very selective aspect the moisture of this product in absorption blood, but because this product is accurately to be poured on the wound, and must from wound, carefully rinse out afterwards, so this product is not to concentrate the best product that can strengthen agglomerative blood constituent.

Now still seek biocompatible, can stop blooding excellently and can be made into the various hemostatic materials that are applicable to the form that various wound bleedings are controlled.Not only use, and in the traumatism treatment field, also seeking such hemostatic material for surgical operation.In vascular surgery, owing to involve blood vessel, hemorrhage is the problem of special trouble.In operation on heart, multiple angiostomy and cannulation site (it is complicated because of the coagulopathy that causes of extracorporeal bypass) can cause having only by local hemostatic could control hemorrhage.Be difficult to control in the operation on vertebra of bone, epidural and/or subdural hemorrhage or hematomyelia by sewing up or burning, rapidly and effectively the probability that hemostasis can the minimum injury nerve root and shorten operating time.In operation on liver, for example live body liver transplantation or cancerous tumour excision has huge continuous risk of bleeding.Effectively hemostatic material can greatly improve the success rate of patient in this class operation.Even under the little situation of amount of bleeding, effectively hemostatic material also can be desirable, for example in dental operation and other oral surgeries such as exodontia, and in the treatment of scratch and burn etc.

Still needing can be with effective hemostasia products of wieldy form conveying.Before the present invention, porous carrier or porous article for example comprise the non-woven fibrous articles of molecular sieve and hydrophilic oxide.

In the treatment of some disease condition neutralizes some surgical procedures,, usually adopt anticoagulant in order to prevent condensing of patient blood; Wherein the most frequently used is heparin.During such as the periods of extracorporeal circulation in the surgical procedures of cardiac operation under direct vision, heparin can the high concentration administration.In these operations, (Activated Clotting Time ACT) monitors these high-caliber heparin and other coagulation parameters with other coagulation assays based on terminal point (endpoint) often to use AcCT.

1966, summarized from the internist Paul Hattersley in California and to have utilized microgranule to carry out the design and the usage of the fresh whole blood coagulation experiment of contact activation.Its objective is and have the quick test result of promotion in the time of clinical meaning.The experiment that Hattersley describes be included in be equipped with in advance the 12mg activator (kieselguhr,

) test tube in add 1ml or more blood.Before admitting patient's blood sample, test tube is preheated to body temperature (37 ℃).When blood entered test tube for the first time, timer picked up counting.Fill test tube, upset is for several times to provide mixing.Then test tube is put into 37 ℃ water-bath.In the time of 1 minute and per thereafter 5 seconds test tube is shifted out from water-bath and tilt, so that blood is distributed on the whole test tube length.Occur for the first time undoubted condensing that timer stops timing during sign.Numerous improvement have been carried out in the ACT experiment of determining the whole blood coagulability for many years, comprised the experimental apparatus of improvement.The various activators that comprise kieselguhr, Kaolin, bead and silica gel have been used in described experiment.Use the experiment that similarly is called APTT (activated partial thromboplastin time) to test the coagulability of blood plasma.Though before more than 40 years, developed the ACT experiment for the first time, but followingly true up to date just found also to be documented in the patent application of submitting on the same day with the application, promptly be used for activator in these types of laboratory test blood clotting very effective aspect the blood coagulation that impels human and animal's wound by the research group identical with the present invention.

Still need can be wieldy effective hemostasia products of carrying of form.Before the present invention, porous carrier or porous article for example comprise the non-woven fibrous articles of inorganic material, are not used as hemostasis device.Discovery now, this class hemostatic article that comprises molecular sieve or inorganic material can provide following characteristics: simple, effective hemostasis of application and minimizing patient are exposed to the situation of the high-temperature lifting that is caused by high heat of adsorption.These products also can be used for can not using in the surgical operation application of Powdered molecular sieve or hydrophilic oxide product.

Summary of the invention

Comprise the adsorbent that hemostatic properties is provided or the hemostatic article of inorganic material and porous carrier by use, the present invention has solved all weak points of the said goods in fact, and wherein said carrier can be to weave or non woven fibre, sheet material or casting films (cast film).Active component is introduced the problem that zeolite product runs into that contains that has solved in the porous carrier such as the QuikClot of Z-Medica.Heat of adsorption can be moved away by the use point from hemostatic article promptly, thereby user should not stand in fact to cause the discomfort that temperature raises and caused by heat of adsorption.Described active component is completely contained in the porous carrier, makes to remove the required removing amount minimum of this product from wound.

When porous carrier be include fibrillation, high surface area fiber and when glassware for drinking water had the sheet material (and adsorbent) of the material of high selectivity, can cause the more effective of blood constituent to concentrate, its further enhancing condenses, and surpasses the viewed situation of other products.The porous chips of complying with irregular surface that comprises adsorbent also can be used to the wound and the injury region that are difficult to arrive at an easy rate.The required characteristic of other wound dressings can directly be introduced in described as (biocidal) activity of killing livestock, and perhaps directly introduces to comprise in the dressing of this class sheet.

The detailed description of invention

Hemostasis be exactly stop hemorrhage, no matter be by normal vasoconstriction, abnormal obstruction, or by condensing or modus operandi.By the hemostasis of condensing (being the target of product of the present invention) is to rely on blood plasma to condense and the complex interactions of the fine albumen of haemolysis, platelet and blood vascular system.The invention provides with the system response that stops blooding with treatment or prevent hemorrhage compositions and material.Particularly, compositions in the preferred embodiment and material cause blood clotting.

Carrying hemorrhage effectively to wound is being in the Wound healing and bone regeneration of feature with tremulous pulse or venous hemorrhage, and particularly desirable in the very debatable surgical procedures of hemorrhage control meeting, for example high surface area, serious tremulous pulse or venous hemorrhage, exudative wound and in organ breach or excision.The compositions of preferred embodiment and material include but not limited to having many advantages aspect the wound conveying hemorrhage, use and remove simple, biological adsorb potentiality, suturing ability, antigenicity and tissue reactive.

According to the character of wound and the Therapeutic Method of utilization, apparatus of the present invention can adopt different forms.For example, for control tremulous pulse or venous active hemorrhage, or the internal hemorrhage in the control laparoscopic surgery, preferably puff (puff), for example cotton balls, fleece (fleece) or form of sponge.In the neurosurgery that usually meets with exudative brain injury mouth, the hemostatic article of sheet form can be preferred.Similarly, in tumor operation, especially in the liver neoplasm operation, can preferably adopt the hemostatic article of sheet form or form of sponge, place it in the tumor bed or on control and ooze out.In dermatological applications, the sheet form can be preferred.During perforation in sealing blood vessels, puff form is normally preferred.Suture form, for example micro suture line or big stitching thread (macrosuture) can be preferred in some applications.Although multi-form conveying is different with processing feature, described device can be configured to hemorrhage on the diseased region effectively, and causes tampon formation fast by thrombocyte adhesiveness, platelet activation and blood clotting.

Can be with the material of the porous carrier that acts on adsorbent or inorganic hemostatic material any can load effective dose adsorbent, and can be applied to the goods of the specific wound of being treated.This porous carrier can comprise natural or synthetic material, and can be woven or non-woven fibre, perforate (open-cell) foamed materials or the like.Comprise adsorbent or inorganic material nonwoven articles can by textile-, paper-, extrusion type and multi-method combination or mix prepares.This product can prepare by using various fibers, and described fiber comprises cellulose, aromatic polyamides, acrylic acid, polyolefin, comprises polyethylene and the polypropylene and the Spectra of fibrillation ^TMCellulose fibre such as the Lyocell and the artificial silk of polyethylene (Honeywell product), chemical modification, and comprise Zylon ^TMOther interior nature/synthetic polymers (Zylon also is PBO, and is consistent with its chemical constitution, poly-(to phenylene-2,6-Ben Bing Er oxazole)).The Zylon fiber that adopts among the present invention forms fibril by Connecticut technical fiber technology (Engineered Fibers Technology of Connecticut), and is sold by the Toyobo Chemical of Japan.Another kind can be used for fiber of the present invention by

Make, it is liquid crystal polymer (LCP) fiber, the equilibrated character that this fiber provides other high-performance fibers not compare.By directly being dissolved in, raw cellulose made Lyocell in the amine oxide solvent.This solution is filtered, be expressed in rare amine oxide water-bath, and condense into fibers form.When preparing described, also can use various binding agents (binder), some of them to have and to assist the functional group of the reinforcing agent release of condensing.

Can be used to form any materials in the adsorbent of hemostatic article or the material that inorganic material is those effective blood coagulations.The nonrestrictive example of these adsorbents is zeolite-type molecular sieves and non-zeolitic molecular sieves.Described inorganic material can comprise kieselguhr, glass dust or fiber, precipitated silica or fumed silica, montorillonite clay, Kaolin.Zeolite is the crystalline aluminosilicate compositions, and it is a microcellular structure, and has by the shared AlO in angle ₂And SiO ₂The three-dimensional oxide framework that tetrahedron forms.Naturally occurring and synthetic zeolite can use.The non-limitative example of spendable zeolite is the zeolite family of structure types such as X, Y, A, β.What comprise in these zeolites is the zeolite of direct synthetic state and the zeolite that has carried out the Ca exchange with other cationes (as Ca).Non-zeolitic molecular sieves is not comprise Al ₂O ₃And SiO ₂Tetrahedron is as the basic framework ingredient but demonstrate the ion exchange of zeolite and/or the molecular sieve of characterization of adsorption.

In certain embodiments of the invention, the adsorbent of selecting may be effectively with other but is in use caused the adsorbent of higher heat of adsorption to be compared, and has lower heat of adsorption.This adsorbent or inorganic material can be packed in the sheet with very wide concentration range, and concentration is that 1wt-% arrives above 95wt-%.The size that is used to prepare described fiber and adsorbent or inorganic material can be in very wide range, from being low to moderate nanometer materials to the pearl that is shaped or the extrudate of pulverizing.In order to obtain activity and functional product, described may need heat-activated, to drive away residual moisture.Then this product is encapsulated in the container of sealing and uses up to needs.The sheet that comprises adsorbent or inorganic material can be directly applied to impaired loci then, realize its advantage aspect promoting to condense.

Preferably, when having determined when to obtain required functionality be desirable, the fiber fibrillation (fibrillate) that the present invention is adopted increasing surface area, and improves the adsorbent that keeps higher or the ability of inorganic material and other additive loadings.The fibril that is fit to formation property (fibril-forming) thermoplastic polymer can comprise polymer and the copolymer that is derived from vinyl chloride, vinylacetate, acrylonitrile, styrene, butadiene, vinylidene chloride, ethylene and propylene, and condensation polymer, for example polyamide and polyester, for example polyester of two pure and mild aromatic dicarboxilic acids.Also can use the mixture of fiber formation property (fiber-forming) thermoplastic, polymeric materials.The hot melt that is fit to can include, but are not limited to: EVA (vinyl-vinyl acetate copolymer) hot melt (for example copolymer of EVA), polyolefin hot melt, polyamide hot melt, pressure sensitive hot melt, styrene-isoprene-phenylethene (SIS) copolymer, s-B-S (SBS) copolymer, ethylene-ethyl acrylate copolymer (EEA), polyurethane reactive (PUR) hot melt or the like.Also can use poly-(Wan oxazolin) hot melt compounds.

Can use the single hemostatic substrate that constitutes porous carrier of the present invention, or the combination of this class hemostatic substrate.Multiple different substrate forms can be preferred, for example puff, fleece, fabric or sheet, sponge, stitching thread or powder.In this manual, term " fleece " uses as the broad terms with its its ordinary meaning, and comprises any softish, ductile or similar fibrous material that is processed into.Can provide the fleece of (but being not limited to) following form: the form of non-woven form or puff, ball or sheet.Should be appreciated that and to handle in any suitable manner or the coated fiber fleece improves its hemostatic properties.Term " puff " also uses as the broad terms with its its ordinary meaning, and comprises any fibrous material of being arranged to soft ball or liner form.Puff can be constructed with fleece.Term " sponge " also uses as the broad terms with its its ordinary meaning, and comprises the fluidic material that is configured to absorb such as blood.Sponge can be used, but is not limited to, and fleece, puff, fiber, fabric or the like be structure separately, perhaps constructs with the combination of another material.Can use different matrix to form the uniform homogeneous blend of material, perhaps can prepare complex matrix by 2 kinds or how different one-tenth mold bases.In certain embodiments, may be desirable be in used adsorbent of the present invention or inorganic material hemorrhage, to add auxiliary hemorrhage.Any suitable hemorrhage can be deposited on the matrix of preferred embodiment.The polysaccharide microsphere that available auxiliary hemorrhage is biological absorbable micropore, concentrate of coagulation factors, the reorganization VIla factor

Alphanate FVIII concentrate; Bioclate FVIII concentrate; Monoclate-P FVIII concentrate; Haemate P FVIII; Von Willebrand factor concentrate; Helixate FVIII concentrate; Hemophil-M FVIII concentrate; Humate-P FVIII concentrate; Hyate- Porcine FVIII concentrate; Koate HP FVIII concentrate; The kogenateFVIII concentrate; Reorganization FVIII concentrate; Mononine FIX concentrate; With fibrogamminP FXIII concentrate.This class hemorrhage can any suitable form (powder, liquid, respective pure form, in suitable excipient, on suitable carriers or the like) is applied to described matrix.

Can use the combination of single hemorrhage or multiple hemorrhage.According to the character of matrix and hemorrhage, the form of matrix and the character of the wound for the treatment of, the preferred hemorrhage load level on the matrix can change.

According to the above-mentioned method for preparing the puff of stopping blooding, can be by the fiber production hemostatic textile.Usually a preferred side has smooth surface and opposite side has the fabric of rough surface.Yet in certain embodiments, preferably both sides have the fabric of rough surface, for example are used for relevant with irregular wound or depths wound, fatal as possibility injury of groin.In preferred embodiments, rough surface is exposed to wound, thereby makes the maximum that contacts of fiber and wound, produces the adhesion to wound that the anastalsis improved is become reconciled, and the contacting of adsorbent and wound blood flow.Comprising load in preparation has in the hemostatic textile of fiber of adsorbent or inorganic material, usually preferred gained fabric comprises adsorbent or the inorganic material of 1-95wt-%, more preferably 5wt-% to the adsorbent of 90wt-% or inorganic material and most preferably 50wt-% to adsorbent or the inorganic material of 80wt-%.Yet, in certain embodiments, adsorbent that can preferred higher or lower level.If use additional hemorrhage, or other compositions in described fiber or other matrixes to be added, can preferably different load levels.

The hemostatic textile of the sheet form of pre-selected size can be provided.Selectively, can shear, prune or fold bigger hemostatic textile sheet, so that the size and dimension that is fit to wound to be provided.Selectively, the sheet after pruning can be stacked into multilamellar or laminated.Though described hemostatic textile is biocompatible in skin or topical application, after reaching satisfied degree of hemostasis, it can be removed from wound, maybe it can be stayed original position up to Wound healing.Hemostatic textile can be used as artificial skin, and/or antibiotic property can be provided.But can prepare sthptic sponge according to method well known in the art, that prepare mandruka by the polymeric material of biocompatible or bio-absorbable.These class methods generally include the solution of preparation polymeric material, cross-linking agent and foaming agent.Can in the forming process of sponge, make its load adsorptivity hemorrhage.

Though preferably hemostatic material (for example hemostatic textile, sponge, puff or the powder for preparing as mentioned above) is directly applied to wound usually, and this hemostatic material demonstrates gratifying adhesiving effect to polytype wound, but can preferably this hemostatic material introducing be comprised in the wound dressing of other compositions in certain embodiments.

Remain adhered on the wound in order to ensure this hemostatic material, can use suitable binding agent, for example along the edge of hemostatic textile, sponge or puff one side.Though can use any being applicable to form bonded binding agent, the preferred usually pressure sensitive adhesives that uses with skin.Contact adhesive is normally defined applying light and just is adhered on the matrix, does not stay remaining binding agent when still removing.Contact adhesive includes, but are not limited to, but the solvent in the solution adhesive, hot-melt adhesive, water-based emulsion bond calendering (calenderable) binding agent, and radiation-curing binders.To most of purposes,, thereby be preferred because the solution adhesive use is simple and have multifunctionality.Hot-melt adhesive is usually based on the block copolymer of resin-bonded (resin-tackified).Water-based emulsion bond comprises those binding agents with acrylic copolymer, butadienestyrene copolymer and natural rubber latex preparation.Radiation-curing binders is made up of acrylic acid oligomer and monomer usually, and this binding agent solidify to form contact adhesive when being exposed to ultraviolet.

In the contact adhesive the elastomer of normal use comprise natural rubber, styrene-butadiene latex, polyisobutylene, butyl rubber, acrylic resin, and silicones.In preferred embodiments, use is based on the contact adhesive of acrylate copolymer or silicones.Acrylate copolymer has low level of allergenicity usually, removes from skin easily, has low abnormal smells from the patient, and demonstrates low machinery and chemical stimulation rate.Because its biocompatibility, the medical grade silicone contact adhesive is preferred.

The factor that influences the suitability of contact adhesive in the wound dressing of preferred version comprises: do not contain the skin irritation composition, fully cohesive strength so that this binding agent can thoroughly remove, not have over-drastic mechanicalness skin irritation from the skin and can adapt to the ability of skin movements and the well tolerable property of body fluid.In preferred embodiments, this contact adhesive comprises butyl acrylate.Though butyl acrylate pressure sensitive adhesives is normally preferred in many application, any being suitable for can be used in conjunction with the contact adhesive of skin.This class contact adhesive is well known in the art.

As mentioned above, the hemostatic material of preferred embodiment demonstrates the good adhesion to wound usually, thereby binding agent is not essential as contact adhesive.Yet,, can preferably use contact adhesive for easy to use and guarantee that this hemostatic material remains on the fixed position after being applied to wound.

Though the hemostatic textile in the preferred embodiment and other hemostatic materials have shown excellent mechanical intensity and Wound protection usually, in certain embodiments, preferably use support material or other materials in a side of hemostatic material.For example, can prepare and comprise 2 layers or more multi-layered complex, wherein one deck is a hemostatic material, another layer be for example elastomer layer, gauze, steam permeability film, waterproof membrane, weave or supatex fabric, reticulate body or the like.Can connect these layers with any suitable method then, binding agent for example is as contact adhesive, hot-melt adhesive, curable adhesive; And use heat or pressure, as in lamination; By using the physical bond of stitching, snap-fastener, other securing members or the like.

By carrying out extra sense ion such as the exchange of Ca++, can utilize the surface charge characteristics of fiber and filler to help condense.Add the anionic polymerisation electrolyte and also can increase ion-exchange capacity.Also can change described fibrous and original fiber degree strengthens and optimization is condensed.Also can with extra biological activity filler as discharge the ionic activity glass of Ca, Ag introduce as described in slice in.

One of more effective embodiment of the present invention comprises to be introduced the aramid fibre of 5A powder and microfibrillated in the non-woven sheets made from the papermaking process technology.Described zeolite-loaded amount is 65-75wt-%.This sheet is activated in blanket of nitrogen at a certain temperature, be stored in then in the gas-tight container of sealing.Take out this sheet then from container, and it is directly applied to wound hemostasis.In case arrest hemorrhage, and patient stablized, then further clean wound.

Researcher believes that hemostasis device of the present invention does not need extra hemorrhage effectively to realize the control over bleeding function of (comprising that important internal is hemorrhage).Therefore, the hemostasis device of the present invention that does not further comprise hemorrhage has good heat stability, and can store the several months and need not cold preservation by several years and can not lose efficacy.Even under the situation of not cold preservation, each embodiment also all can promptly store one long period with state, and therefore this class embodiment of the present invention is applicable to various medical conditions, and is particularly useful for open-air and urgent the use.Compare and comprise the hemostasis device that extra hemorrhage reaches the styptic activity level of comparability, the manufacturing of this class device of the present invention and/or use also relatively cheap.In certain embodiments, hemostasis device of the present invention also comprises one or more therapeutic agents for the treatment of effective dose, for example promotes the medicament of wound healing.Promote the medicament of wound healing to comprise: the antibiotic medicine, as suppressing medicament, the hydryllin of leucocyte migration to the operation damage field; Suppress the medicament that free radical forms; With bacterial inhibitor or antibacterial.Usually, the treatment effective dose refers to postpone the required amount of disease specific situation of showing effect, holding back the development or interrupting fully being treated.Usually, the treatment effective dose changes along with the nature and extent of age, disease condition and the sex of individuality and experimenter's disease condition, and these factors can be determined by those skilled in the art.Can adjust the dosage of therapeutic agent that hemostasis device of the present invention comprises, to adapt to concrete experimenter and the disease condition of being treated.Phrase used herein " medicament of promotion wound healing " refers to the medicament of the normal healing process of its administration meeting accelerated in wounds.Promote the medicament of wound healing to comprise the antibiotic medicine, suppress medicament and bacterial inhibitor or antibacterial that free radical forms.

The antibiotic medicine is to suppress or the interior immunoreactive medicament of prevention body, comprising: (i) suppress medicament (" leucocyte migration inhibitor ") and the hydryllin of leucocyte migration to the surgical operation damage field.Representational leucocyte migration inhibitor comprises silver sulfadiazine, aspirin, indometacin and Nafazatrom (coming method to look into shape).Representational hydryllin comprises pyrilamine, chlorphenamine, tetrahydrozoline, antazoline, reaches sulfide of other antibiotic medicine such as cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, andrographolide, omcilon, indometacin, sulindac, its salt and correspondence or the like.

The medicament that representational inhibition free radical forms comprises that inhibited oxidation produce thing forms and/or antioxidant, superoxide dismutase (SOD), catalase, glutathion peroxidase, b-carotene, ascorbic acid, siderophillin, ferritin, ceruloplasmin and the deferoxamine alpha-tocopherol of effect.

Representational bacterial inhibitor or antibacterial comprise: antibiotic substance, as beta-Lactam antibiotic, for example cefalotin, n-formamido (formamidoyl) thienamycin and other thienamycin derivants, tetracycline, chloromycetin, neomycin, Gramicidin, bacitracin, sulfonamide; Aminoglycoside antibiotics, for example gentamycin, kanamycin, amikacin, sisomicin and tobramycin; Nalidixic acid and analog, for example antibacterial of norfloxacin and fludalanine/pentizidone combination; Nitrofural or the like.

Hemostasis device of the present invention can comprise one or more therapeutic agents, and this therapeutic agent can use separately or make up with one or more hemorrhages.

Randomly, various additives can be introduced in the hemostasis device of the present invention, and can significantly do not reduced the styptic activity of these devices.Term used herein " medicine acceptable carrier " refers to that one or more are fit to compatible solid or liquid filling agent, diluent or encapsulated substance to human administration.Term " carrier " refers to organic or inorganic composition (natural or synthetic), and active component is with it in conjunction with can conveniently using.The composition of pharmaceutical composition also can be blended in the woven sheet of the present invention with ad hoc fashion, and is mixed with each other, and this mode makes and do not have the interaction that can significantly weaken required styptic activity.

Known additive of professional field of papermaking (for example keeping auxiliary agent) and binding agent are joined in the molecule screening the pulp together or in succession, improve the reservation amount of molecular sieve composition in fibre substrate, and improve the intensity of paper.This class additive comprises starch, polyvinyl alcohol (PVA), acrylic resin, and microcrystalline Cellulose (for example: carboxymethyl cellulose).The addition of organic additive is 5% weight that fiber adds molecular sieve total amount (200 ℃ of bases).These additives can add in the make-up tank with refined fiber and/or add in the flow box (head box).Preferred flocculation system is to comprise poly--DADMAC coagulating agent, cationic, low-molecular-weight polyelectrolyte, and anion-polyacrylamide (a-PAM), high molecular polyelectrolyte, two chemical formulations (dual chemical recipe).

Paper of the present invention can be from the aromatic polyamides paper pulp of DuPont and Twaron manufacturing, the CFF that Sterling Fiber makes ^TMAcrylic acid paper pulp, Celanese makes, the Vectran of Engineered FibersTechnology fibrillation ^TMThe Lyocell pulp preparation of LCP paper pulp and Engineered FibersTechnology fibrillation.Pattern can comprise the inorganic material of 75-90wt-% or molecular sieve filled dose.

Having, the paper of high water absorbing capacity is the Vectran with 90wt-% zeolite ^TMManual sheet (hand sheet).The most high-load aramid paper has the Y-54 of 84wt-%.The Lyocell paper and the CFF that has up to 78wt-% Y-54 zeolite that have up to 84wt% Y-54 zeolite have also been prepared ^TMAcrylic acid paper.

Embodiment

Shown in following calcium exchanging zeolite embodiment, tested the effectiveness of hemostatic article of the present invention.The scraps of paper have been prepared with mixture (mixing very abundant) with the blended 4.84 gram aromatic polyamides paper pulp of number premium on currency.(UOP LLC, Des Plaines IL), and fully mix to add 5.09 gram calcium ZB-100 zeolites then.Adding 0.4526 gram DADMAC (diallyldimethylammonium chloride) further mixes.Water is this mixture diluted to 3.0 liter, and adds in the Techpap paper machine.Also added the Percol E38 solution that contains the solid 100 times of dilutions of 0.325wt-%.Cast, roll and dry paper.Then according to the hemostatic capability of following method test paper.

Test blood sample in order to following scheme.

The instrument that uses is the Haemoscope company of Illinois Morton Grove

Analyser.This apparatus measures is up to the time that forms initial fibrin, the kinetics of initial fibrin grumeleuse that reaches maximum intensity and the final strength and the stability of fibrin grumeleuse, thereby measure the ability of its (mechanicalness stops hemorrhage, and unsuitable thrombosis does not take place) work of stopping blooding.To non-activated sample:

I. pipette (pipet) 360uL to beaker from red capped (capped) test tube, beginning TEG test.

To activatory sample:

I. at first, obtain the zeolite pattern that contains to be tested from laboratory.They should be weighed, bottle, use oven activated (if desired), and before the experiment beginning, add a cover.Bottling contains zeolite pattern 2 times for the need test volume.For example, if passage 2 will be tested paper and blood that 5mg contains zeolite, the amount that is used for the bottle of passage 2 so is weighed as 10mg.For the 10mg sample, weigh up 20mg or the like.Reason is referring to following note.

Ii. for once activation operation, once test three patterns that contain zeolite.The non-additive blood sample that do not activate moves in first passage.Passage 2,3 and 4 is and contains the blood sample that zeolite paper contacts.

Iii. in a single day be ready to experiment, a pipet is made as 720uL, another pipet is made as 360uL.Prepare 3 red capped tube (test tube that does not add the plain polypropylene liner of chemical reagent) and get blood, and prepare 3 extra red capped tube to pour the pattern that contains zeolite into.

Iv. get blood from volunteer, take back analyser to TEG.First test tube that abandons collection reduces the tissue factor pollution of blood sample.After the donor gets blood, before 4-5 minute, blood sample is contacted with the paper material that contains zeolite and in the TEG instrument, move.

V. opening bottle 1 paper that also will contain zeolite pours in the red capped tube.

Vi. the zeolite paper that contains in test tube adds 720uL blood at once.

Vii. put upside down 5 times.

Viii. the mixture that shifts 360uL blood and contain zeolite paper is packed in the beaker.

Ix. begin the TEG test.

Annotate: blood is double with the initial mixing ratio that contains zeolite paper, because lost the blood of partial volume on the bottle sidewall, and some samples can absorb blood.The blood of 360uL is moved in the beaker to use double volume to guarantee to have at least.We saw contains zeolite paper the ratio of blood is generally 5mg/360uL, 10mg/360uL and 30mg/360uL.

The R (min) of following table report is the time that forms from on-test to blood clot of TEG analyser report.Should

Analyser has the sample cup that constantly shakes back and forth with 4 ° of 45 ' radians by setting speed consistently.Each rotation continues 10 seconds.The 360ul whole blood sample is put into cup, the steady pin of linking on the torsion wire is immersed in the blood.When forming fibrin for the first time, it begins to make described pin and grumeleuse shake synchronously in conjunction with described cup and pin.The acceleration of motion of described pin is the function of kinetics of clot development.Have only when fibrin-platelet in conjunction with described cup with after pin connects together, the torque of rotating cup just is delivered on the buried pin.The bonded intensity effect of these fibrin-platelet the amplitude of described pin motion, thereby strong grumeleuse make described pin directly and beaker be synchronized with the movement.Therefore, the amplitude of output is directly related with the intensity of the grumeleuse of formation.When clot retracts or dissolving, these are in conjunction with destroyed, and the transfer of described cup motion is weakened.Rotatablely moving of described pin is converted to electronic signal by mechanical-electrical converter, and this electronic signal can be arrived by computer monitoring.

The hemostasis distribution curve (profile) of gained is to forming first strand of fibrin required time, the kinetics that forms grumeleuse, clot strength (with the dyn/cm of shearing elasticity unit ²Expression) and the measurement result of clot dissolution.

Sample R (min)

Run (operation) 1 Native (nature)-do not add paper 25.2

Run1-vial act (bottle effect) Ca A paper (paper) 10mg 6.7

Run1-bottle effect Ca A paper 30mg 4.2

Run1-bottle effect Ca A paper 5mg 10.2

The Run2 nature-do not add paper 34.5

Run2-bottle effect CaA paper 30mg 3.6

Run2-bottle effect CaA paper 5mg 6.5

Run2-bottle effect CaA paper 10mg 5.5

Spendable inorganic hemostatic material comprises as follows:

Have the middle hole bioactive glass that calcium silicates is formed, it is prepared by following steps:

The HCl of mixture A-15 gram tetraethyl orthosilicate, 5.0 gram calcium nitrate tetrahydrates, 20.1 gram ethanol, 7.5 gram deionized waters and 2.5 gram 1M.

Mixture B-by 20.02 gram Pluronic P123 triblock copolymers (BASF) being dissolved in the triblock copolymer solution that makes in the 80.12 gram ethanol.

Mixture C-45ml mixture B is added among the mixture A, and passed through electromagnetic agitation 2 minutes.Then this mixture can be heated 16 hours in 60 ℃ of open porcelain crucibles, put into heating furnace then, be heated to 550 ℃, keep four hours, be cooled to 100 ℃ then at 550 ℃ with 3 ℃ of per minutes.This material can be taken out and be cooled to room temperature from heating furnace then.

Diafil 460 has～30m ²The kieselguhr of/g high surface, it can be located at SantaBarbara from general headquarters, California, the World Minerals Inc. of USA obtains.

Adding by the 2M nitric acid with the deionized water of the calcium nitrate tetrahydrate of the tetraethyl orthosilicate of 46.8ml, 21.43g, 45ml and 7.6ml can the synthetic calcium silicate sol-gel glass in the 250ml politef bottle.Subsequently with of short duration this mixture that shakes of hands, sealing and be heated to 60 ℃ kept 50 hours in convection oven then is cooled to 25 ℃ with 0.1 ℃ of per minute afterwards.Remove decap from bottle subsequently, bottle is returned in the baking oven and be heated to 180 ℃ from 60 ℃, kept 12 hours at 180 ℃ afterwards, be cooled to 25 ℃ with 2.5 ℃ of per minutes subsequently with 0.1 ℃ of per minute.Subsequently exsiccant gel is placed porcelain dish, and be heated to 105 ℃ with 0.9 ℃ of per minute in heating furnace, be heated to 160 ℃ with 0.2 ℃ of per minute subsequently, be heated to 500 ℃ with 0.5 ℃ of per minute afterwards, the back is heated to 700 ℃ with 0.1 ℃ of per minute again.Heating furnace was kept 1 hour at 700 ℃, be cooled to 25 ℃ with 10 ℃ of per minutes subsequently.Material after the heating is stored in the exsiccator.

Celite 209 has 10-20m ²The kieselguhr of the medium surface area of/g, it can be located at Santa Barbara from general headquarters, California, the World Minerals Inc. of USA obtains.

Celite 270 has 4-6m ²The kieselguhr of/g low surface area, it can obtain from World MineralsInc..

By 64g dalcium biphosphate monohydrate is heated to 500 ℃ and keep can making calcium polyphosphate glass in 15 hours at 500 ℃ with 10 ℃ of per minutes.Subsequently, this material is heated to 1100 ℃ with 10 ℃ of per minutes from 500 ℃, and kept 1 hour at 1100 ℃.Afterwards fused polyphosphate glass is poured directly in 1 liter the deionized water.Then with gained glass dust 110 ℃ of dryings 1 hour, and in the corundum vibromill, grind to form fine powder.

Siltex 18-97% silica glass fibre cloth-SIL TEX is gang's high performance textiles fabric, it comprises high-purity, high-intensity amorphous silica fibres, be woven into strong, softish fabric, it is designed for the situation that has extreme temperature conditions.

Can be from St.Gobain Group, Courbevoie France obtains to comprise the calcining Zr-Si glass of alkaline-resisting (AR) glass fibre.

Hi-Sil 250-can be from PPG Industries, Pittsburgh, the precipitated silica (silica gel) that Pennsylvania obtains.

Quartz sand is 99% silicon dioxide normally.

Hemostatic article of the present invention provides significant anastalsis, and the variety of issue that the wound contact is caused minimizes.Though described hemostatic article load has a large amount of inorganic material, but wound no longer resembles adsorbent or inorganic material and directly applies to and directly be exposed to adsorbent or inorganic material the wound, therefore allows to use the little but wound of continuous bleeding and prestige and life of this product treatment.In addition, in the non-woven sheets form, introduce described adsorbent or inorganic material and make and in surgical procedures, to use this product effectively to stop blooding, thereby make the surgeon more to be absorbed in to perform the operation rather than take much time control over bleeding.

Except that non-woven sheets, other forms of material also is considered to belong in the scope of the invention, comprises film, and wherein the mixture of adsorbent or inorganic material combines with polymer and forms film, and it can be applied to wound to be used for hemostasis.Can use the haemostatic effect that provides required, various adsorbents or the inorganic material that reduces the combination of heat of adsorption and biocompatibility.

Claims (10)

1. the hemostatic article that comprises porous carrier and adsorbent or inorganic material compositions.

2. hemostatic article according to claim 1, wherein said porous carrier is selected from weaving fiber goods, non-woven fibrous articles, puff, sponge, and composition thereof.

3. hemostatic article according to claim 2, wherein said porous carrier be for weaving or non-woven fibrous articles, and this fiber is selected from the cellulose fibre of aromatic polyamides, acrylic resin, cellulose, polyester, chemical modification, and composition thereof.

4. hemostatic article according to claim 1, wherein said adsorbent is zeolite molecular sieve or non-zeolite molecular sieve, and described inorganic material is selected from kieselguhr, glass dust or fiber, precipitated silica or fumed silica, Kaolin and montorillonite clay, and the permutite of calcium exchange.

5. hemostatic article according to claim 4, wherein said molecular screening is from zeolite X, Y, A, β and composition thereof.

6. hemostatic article according to claim 1 also comprises calcium ion.

7. hemostatic article according to claim 1 also comprises the biological activity filler to discharge calcium or silver ion or its mixture.

8. hemostatic article according to claim 1, the structure of wherein said hemostatic article is selected from binder, stitching thread, dressing, gauze, gel, foamed materials, net, film, band or diaphragm.

9. hemostatic article according to claim 1, also comprise reagent, this reagent is selected from analgesic, steroid, hydryllin, anesthetis, antibacterial, disinfectant, antifungal, vasoconstrictor, hemorrhage, chemotherapeutic, antibiotic, keratolytic, cauterant, antiviral drugs, epidermal growth factor, fibroblast growth factor, transforming growth factor, glycoprotein, fibrinogen, fibrin, wetting agent, antiseptic, lymphokine, cytokine, odour controlling materials, vitamin, and thrombin.

10. the method for treatment mammal wound is included in and places the described hemostatic article of arbitrary claim among the claim 1-9 on the described wound.